Throughout this application, various publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The chemistry and pharmacology of the potent anticancer diterpenoid taxol 1 (1), isolated from the yew tree, Taxus brevifolia, has been reviewed extensively (2, 3, 4, 5). Taxol is currently undergoing phase II trials (6) and has shown very encouraging antitumor activity, especially against ovarian and breast cancers (4, 5).
Unfortunately, the natural availability of taxol is extremely limited. The increasing demand of taxol for the treatment of patients and the desirability of analogs to determine the real pathway of its mode of action has made the total synthesis or hemi-synthesis of taxol and its analogs a high priority over the last ten years (2, 3, 7).
Attempts at the hemi-synthesis of taxol have been based on using an extract from the leaves of the yew tree, 10-deacetylbaccatin III, as the starting material (3). Structural modifications of taxol have also been performed using taxol as the starting material itself, or 10-deacetylbaccatin III (3). In addition, there has been limited success in synthesizing the taxane skeleton or framework (2, 3, 7).
However, due to the complex structure of taxol, i.e. the vast functionalities and the buildup of the highly strained middle ring system, the various efforts at the total syntheses of this tetracyclic compound have not been successful (2, 3).
The inventors have overcome the difficulties faced by others and have been able to synthesize taxol via three routes. The present invention provides three basic routes for the total synthesis of taxol, important intermediates as well as analogues of taxol. These analogues include structures with nortaxane ring systems containing an aromatic moiety in lieu of the taxol C ring.